Research: The research goal of our laboratory is to understand the molecular mechanism of Tumor Necrosis Factor (TNF) signaling and the regulation of cell death. TNF Signal transduction. TNF is a proinflammatory cytokine that plays a critical role in diverse cellular events. Upon TNF treatment, cells could be undergo proliferation, differentiation and apoptosis. In previous study, we found that the activation of transcription factors NF-kB and AP-1 as well as the induction of apoptosis are mediated by three distinct pathways in response to TNF. While the adaptor molecule FADD mediates apoptosis, the death domain kinase RIP and the TNF receptor associated factor TRAF2 are essential for NF-kB and AP-1 activation. While we are continuing to explore the underlying mechanism of TNF signaling, especially about how RIP and TRAF2 transduce TNF signal to their down stream targets, we extended our research on RIP and TRAF2 to cell stress responses such as genotoxic and ER stresses. Our data indicated that RIP protein also plays a critical role in those cell stress responses. Recently, we also found that RIP and TRAF2 play critical roles in ROS-induced cell death. Regulation of cell death. TNF can induce either apoptosis or necrosis in a given tissue ot type of cells. Apoptosis (Programmed Cell Death) is a common phenomenon during development and used to eliminate harmful or unwanted cells from the organism. Necrosis occurs commonly in pathological conditions. Apoptosis is a crucial process for organisms to keep their cellular homeostasis. Deregulation of apoptosis is involved in many diseases, for instance, inefficient apoptosis has been found in many different cancers. Since all cells have the genetic machinery required to commit suicide, the ability to selectively regulate this process has profound implications for treating disease. Because more and more evidence indicates that irregular cell growth often leads to apoptosis, we believe that in addition to the promoting growth signals, inactivation of apoptosis is essential for normal cells to become tumor cells. This can be achieved by either increasing a signal that actively blocks apoptosis or generating a defective mutation in the cell death machinery. Identification of these apoptosis-inactivating targets in different cancers will greatly enrich our knowledge about tumorigenesis and help to develop new cancer therapies. One of our research interests is to identify the genes that protect cancer cells from apoptosis and, upon understanding the mechanisms of their actions, to develop new cancer therapies. To do so, we use tumor necrosis factor (TNF)-mediated apoptosis as a model system. Using several different approaches including microarray, we have identified a novel anti-apoptotic gene,ATIA, which protects cells against TNF-induced cell death.However, during our study with the ATIA knock-out mice generated by us, we found that ATIA plays a dual role in TNF-induced cell death:it protects cells against TNF-induced apoptosis, but on the other hand,it is also required for TNF-induced necrosis. Threfore, our studies on ATIA shed new light on the regulation of TNF-induced cell death. This knowledge will help to develop new strategies to improve the therapeutic value of TNF in treating cancer.